ES2299689T3 - FUSIONED CYCLALQUIL-UERA COMPOUNDS WITH 1,4-DISPOSED BENZO, USEFUL FOR THE TREATMENT OF ILLNESSES BY CYTOKINES. - Google Patents

Abstract

A compound chosen from: 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- (4- {2- [2- (1-phenyl-ethylamino) -pyrimidin- 4-yl] -ethoxy} -naphthalen-1-yl) -urea; 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- {4- [2- (cyclopropylmethyl-amino) -pyrimidin-4-yloxy] -naphthalen-1-yl }-urea; 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- (4- {2 - [(tetrahydro-furan-2-ylmethyl) -amino] -pyrimidin-4- yloxy} -naphthalen-1-yl) -urea; 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- (4- {2 - [(thiophene-2-ylmethyl) -amino] -pyrimidin-4-yloxy} -4-naphthalen-1-yl) -urea; 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- (4- {2- [2- (1-pyridin-2-yl-ethylamino) -pyrimidin-4 -il] -ethoxy} -naphthalen-1-yl) -urea; 4- (2- {4- [3- (5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -pyridine acid ethylamide -2-carboxylic; 4- {4- [3- (5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -pyridine-2-carboxylic acid diethylamide; 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- {4- [2- (2-piperidin-1-ylmethyl-pyridin-4-yl) -ethoxy] -naftalen-1-yl} -urea; 4- (4- {3- [5-tert-Butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -ureido} -naphthalen- acid methyl-phenyl-amide 1-yloxy) -pyridine-2-carboxylic; 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- (4- {2- [2- (1-phenyl-ethylamino) -pyrimidin-4-yloxy] - ethyl} -naphthalen-1-yl) -urea; 4- (2- {4- [3- (5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -morpholine acid ethylamide -2-carboxylic; 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- {4- [2- (2-diethylaminomethyl-morpholin-4-yl) -ethoxy] -naphthalen-1 -il} -urea; 4- (2- {4- [3- (5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} - methyl-phenyl-amide ethyl) -morpholine-2-carboxylic; 1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- (4- {2- [2- (1-phenyl-ethylamino) -pyrimidin-4-yl] -ethoxy} -naftalen-1-yl) -urea; 1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3-4- [2- (cyclopropylmethyl-amino) -pyrimidin-4-yloxy] -naphthalen-1-yl} -urea ; 1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- (4- {2 - [(tetrahydro-furan-2-ylmethyl) -amino] -pyrimidin-4-yloxy} -naftalen-1-yl) -urea; 1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- (4- {2 - [(thiophen-2-ylmethyl) -amino] -pyrimidin-4-yloxy} -naphthalen -1-yl) -urea; 1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- (4- {2- [2- (1-pyridin-2-yl-ethylamino) -pyrimidin-4-yl ] -ethoxy} -naphthalen-1-yl) -urea; 4- (2- {4- [3- (5-tert-Butyl-2-methyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -pyridine-2 acid ethylamide -carboxylic; 4- {4- [3- (5-Tert-Butyl-2-methyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -pyridine-2-carboxylic acid diethylamide; 1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- {4- [2- (2-piperidin-1-ylmethyl-pyridin-4-yl) -ethoxy] -naphthalen -1-yl} -urea; 1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- (4- {2- [2- (1-phenyl-ethylamino) -pyrimidin-4-yloxy] -ethyl} -naftalen-1-yl) -urea; 4- (2- {4- [3- (5-tert-Butyl-2-methyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -morpholine-2 acid ethylamide -carboxylic; 1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- {4- [2- (2- diethylaminomethyl-morpholin-4-yl) -ethoxy] -naphthalen-1-yl }-urea; 4- (2- {4- [3- (5-tert-Butyl-2-methyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) methyl-phenyl-amide -morpholine-2-carboxylic; 4- (2- {4- [3- (5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -morpholine acid methylamide -2-carboxylic; 4- (2- {4- [3- (5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -morpholine acid dimethylamide -2-carboxylic; 4- (2- {4- [3- (5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -morpholine acid phenylamide -2-carboxylic; 2- [4- (2- {4- [3- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -morpholin -2-yl] -N, N-dimethyl-acetamide; 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- {4- [2- (2-phenyl-morpholin-4-yl) -ethoxy] -naphthalen-1 -il} -urea; 1- {4- [2- (2-Benzyl-morpholin-4-yl) -ethoxy] -naphthalen-1-yl} -3- (5-tert-butyl-2-p-tolyl-2H-pyrazole-3 -il) -urea; 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- {4- [2- (2-phenethyl-morpholin-4-yl) -ethoxy] -naphthalen-1 -il} -urea; 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- {4- [2- (2-phenoxymethyl-morpholin-4-yl) -ethoxy] -naphthalen-1 -il} -urea; 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- (4- {2- [2- (1-phenyl-ethyl) -morpholin-4-yl] - ethoxy} -naphthalen-1-yl) -urea.

Description

Cycloalkyl urea compounds fused with 1,4-disubstituted benzo, useful for treatment of cytokine-mediated diseases.

Request Data

This request claims to benefit from the provisional application No. 60 / 359,809 of the United States, deposited dated 2/25/2002.

Technical scope of the invention

This invention relates to urea compounds. benzofused 1,4-disubstituted according to claim 1. The compounds of the invention inhibit the cytokine production involved in the processes inflammatory and, therefore, are useful for treating diseases and pathological conditions that lead to inflammation, for example the chronic inflammatory disease This invention further relates to processes to obtain these compounds and compositions Pharmaceuticals that contain these compounds.

Background of the invention

In PCT patent publications WO 00/55139 and WO 00/43384 aromatic heterocyclic compounds are described, useful for treating certain diseases mediated by cytokines. He tumor necrosis factor (TNF) and interleukin-1 (IL-1) are entities important biological, known as proinflammatory cytokines. These, among other related molecules, mediate the response inflammatory associated with the immunological recognition of Infectious agents. The inflammatory response plays a role important in limiting and controlling pathogenic infections.

Elevated levels of proinflammatory cytokines have also been associated with a large number of autoimmune diseases, for example toxic shock syndrome, rheumatoid arthritis, osteoarthritis, diabetes and inflammatory bowel disease (Dinarello, CA et al., Rev Infect. Disease 6 , 51, 1984). In these diseases, chronic elevation of inflammation exacerbates or causes much of the pathophysiology observed. For example, rheumatoid synovial tissue is invaded by inflammatory cells, which cause destruction of cartilage and bone (Koch, AE et al., J. Invest. Med. 43 , 28-38, 1995). Studies suggest that cytokine-mediated inflammatory changes may intervene in the pathogenesis of endothelial cells, including restenosis after percutaneous transluminal coronary angioplasty (PTCA) (Tashiro, H. et al., Coron. Artery Dis. 12 (2), 107-13, March 2001). An important and therapeutically accepted strategy of potential pharmacological intervention of these diseases consists in the reduction of inflammatory cytokines, for example TNF (also known for its secreted non-cellular form, called TNFα) and IL-1β. A large number of anti-cytokine therapies are currently in clinical trials. Efficacy on monoclonal antibodies directed against TNFα has been demonstrated in a large number of autoimmune diseases (Heath, P., "CDP571: An Engineered Human IgG4 Anti-TNFα Antibody", IBC Meeting on Cytokine Antagonists, Philadelphia, PA, April 24-5, 1997). These include the treatment of rheumatoid arthritis, Crohn's disease and ulcerative colitis (Rankin, ECC et al., British J. Rheum. 35 , 334-342, 1997 and Stack, WA et al., Lancet 349 , 521- 524, 1997). It is believed that the monoclonal antibody works by fixing both soluble TNFα and membrane bound TNF.

A soluble TNFα receptor that interacts with TNFα has been designed. The strategy is similar to that described above for monoclonal antibodies directed against TNFα; both agents are fixed on soluble TNFα, thus reducing their concentration. A version of this construct, called Enbrel (Immunex, Seattle, WA) has recently demonstrated its effectiveness in the phase III clinical trial for the treatment of rheumatoid arthritis (Brower et al., Nature Biotechnology 15 , 1240, 1997). Another version of TNFα receptor, Ro 45-2081 (Hoffmann-LaRoche Inc., Nutley, NJ) has proven effective in several animal models of allergic lung inflammation and acute lung injury. Ro 45-2081 is a recombinant chimeric molecule, constructed from the 55 kDa human TNF receptor fused with a pendant region of the long chain IgG1 gene and expressed in eukaryotic cells (Renzetti et al., Inflamm. Res. 46 , p. 143, 1997).

IL-1 is considered to be involved as an immune effector molecule in a large number of pathological processes. The IL-1 receptor antagonist (IL-1ra) has been examined in human clinical trials. Its efficacy has been demonstrated for the treatment of rheumatoid arthritis (Antril, Amgen). In the phase III human clinical trial, IL-1ra reduces the percentage of mortality in patients suffering from septic shock syndrome (Dinarello, Nutrition 11 , 492, 1995). Osteoarthritis is a progressive, slow disease characterized by the destruction of articular cartilage. IL-1 has been detected in synovial fluid and in the cartilage structure of osteoarthritic joints. It has been found that IL-1 antagonists decrease the degradation of cartilage structure components in a large number of experimental models of arthritis (Chevalier, Biomed. Pharmacother. 51 , 58, 1997). Nitric oxide (NO) is a mediator of cardiovascular homeostasis, neurotransmission and immune function; It has recently been shown that it has important effects on the modulation of bone remodeling. Cytokines, for example IL-1 and TNF, are potent stimulators of NO production. NO is an important bone regulatory molecule, with effects on osteoblast and osteoclast lineage cells (Evans, et al., J. Bone Miner. Res. 11 , 300, 1996). The promotion of the destruction of beta cells, which leads to insulin-dependent diabetes mellitus, is dependent on IL-1. Some of these lesions may be mediated by other effectors, for example prostaglandins and thromboxanes. IL-1 can initiate this process by controlling the level of both cyclooxygenase II and the expression of nitric oxide inducible synthetase (McDaniel et al., Proc. Soc. Exp. Biol. Med. 211 , 24, 1996) .

Inhibitors of cytokine production are expected to block the expression of inducible cyclooxygenase (COX-2). It has been found that cytokines increase COX-2 expression and is believed to be the isoform of the cyclooxygenase causing inflammation (MK O'Banion et al., Proc. Natl. Acad. Sci. USA 89 , 4888, 1992). It is expected, therefore, that cytokine inhibitors, for example IL-1, display their efficacy against those disorders that are usually treated with COX inhibitors, for example family NSAIDs. These disorders include acute and chronic pain as well as symptoms of inflammation and cardiovascular disease.

The elevation of various cytokines has been demonstrated during active inflammatory bowel disease (IBD). An imbalance of IL-1 and IL-1ra is observed in the intestinal mucosa in IBD patients. The insufficient production of IL-1ra greatly contribute to the pathogenesis of IBD (Cominelli et al., Aliment. Pharmacol. Ther. 10 , 49, 1996). Alzheimer's disease is characterized by the presence of deposits of beta-amyloid proteins, confusing neurofibrillar masses and cholinergic dysfunction throughout the hippocampus region. The structural and metabolic lesion observed in Alzheimer's disease is probably due to the persistent elevation of IL-1 (Holden et al., Med. Hypotheses 45 , 559, 1995). A role of IL-1 in the pathogenesis of human immunodeficiency virus (HIV) has been identified. IL-1ra has a clear relationship with acute inflammatory events as well as different pathological stages of the pathophysiology of the invention of HIV (Kreuzer et al., Clin. Exp. Immunol. 109 , 54, 1997). IL-1 and TNF are involved in periodontic disease. The destructive process associated with periodontic disease may be due to a deregulation of both IL-1 and TNF (Howells, Oral Dis. 1 , 266, 1995).

Proinflammatory cytokines, for example TNF? And IL-1?, Are also important mediators of septic shock and are associated with cardiopulmonary dysfunction, acute respiratory distress syndrome (ARDS) and multiple organ failure. In a study conducted with patients, who are admitted to the hospital with sepsis, a correlation has been found between TNFα and IL-6 levels and septic complications (Terregino et al., Ann. Emerg. Med. 35 , 26, 2000). TNFα is also considered to be involved in cachexia and muscle degradation, associated with HIV infection (Lahdiverta et al., Amer. J. Med. 85 , 289, 1988). Obesity has been associated with a higher incidence of infection, diabetes and cardiovascular diseases. Abnormalities in TNFα expression have been observed in each of the previous pathological conditions (Loffreda et al., FASEB J. 12 , 57, 1998). It has been proposed that elevated levels of TNFα intervene in other similar disorders of food intake, for example anorexia and bulimia nervosa. Pathophysiological parallels have been drawn between anorexia nervosa and cancerous cachexia (Holden et al., Med. Hypotheses 47 , 423, 1996). It has been found that a TNFα production inhibitor, HU-211, improves the healing of closed brain injury in an experimental model (Shohami, et al., J. Neuroimmunol. 72 , 169, 1997). It is known that atherosclerosis has an inflammatory component and it has been suggested that cytokines, for example IL-1 and TNF, promote this disease. In an animal model it has been shown that the IL-1 receptor antagonist inhibits the formation of the fat line (Elhage et al., Circulation 97 , 242, 1998).

TNFα levels are elevated in the respiratory tract of patients suffering from chronic obstructive pulmonary disease and may contribute to the pathogenesis of this disease (MA Higham et al., Eur. Respiratory J. 15 , 281, 2000). Circulating TNFα may also contribute to weight loss, associated with this disease (N. Takabatake et al., Amer. J. Resp. & Crit. Care Med. 161 (4 Pt 1), 1179, 2000). It has also been found that elevated levels of TNFα are associated with congestive heart failure and a correlation has been established between the level and severity of the disease (AM Feldman et al., J. Amer. College of Cardiology 35 , 537, 2000). In addition, TNFα has been implicated in reperfusion injury in the lung (Borjesson et al., Amer. J. Physiol. 278 , L3-12, 2000), in the kidney (Lemay et al., Transplantation 69 , 959 , 2000) and in the nervous system (Mitsui et al., Brain Res. 844 , 192, 1999).

TNFα is also a potent osteoclastogenic agent and is involved in bone resorption and in diseases that involve bone resorption (Abu-Amer et al., J. Biol. Chem. 275 , 27307, 2000). It has also been found to be expressed largely in chondrocytes of patients suffering from traumatic arthritis (Melchiorri et al., Arthritis and Rheumatism 41 , 2165, 2000). It has also been found that TNFα plays a key role in the development of glomerulonephritis (Le Hir et al., Laboratory Investigation 78 , 1625, 1998).

Abnormal expression of nitric oxide inducible synthetase (iNOS) has been associated with hypertension of spontaneously hypertensive rats (Chou et al., Hypertension 31 , 643, 1998). IL-1 has a role in the expression of iNOS and, therefore, can also intervene in the pathogenesis of hypertension (Singh et al., Amer. J. Hypertension 9 , 867, 1996).

It has also been found that IL-1 induces uveitis in rats, which could be inhibited with IL-1 blockers (Xuan et al., J. Ocular Pharmacol. And Ther. 14 , 31, 1998). It has been shown that cytokines, including IL-1, TNF and GM-CSF, stimulate the proliferation of blasts of acute myelogenous leukemia (Bruserud, Leukemia Res. 20 , 65, 1996). IL-1 has been shown to be essential for the development of both irritant and allergic contact dermatitis. Epicutaneous sensitization can be prevented with the administration of an anti-IL-1 monoclonal antibody before epicutaneous application of an allergen (Muller et al., Am. J. Contact Dermat. 7 , 177, 1996). Data obtained from IL-1 knockout mice indicate the critical intervention of this cytokine in fever (Kluger et al., Clin. Exp. Pharmacol. Physiol. 25 , 141, 1998). A large variety of cytokines, including TNF, IL-1, IL-6 and IL-8, initiate the acute phase reaction, characteristic of fever, malaise or indisposition, myalgia, headaches, hypermetabolism Cellular and multiple enzymatic and endocrine responses (Beisel, Am. J. Clin. Nutr. 62 , 813, 1995). The production of these inflammatory cytokines is often quickly followed by trauma or an invasion of pathogenic organisms.

A correlation between other pro-inflammatory cytokines and a large number of pathological conditions has been established. IL-8 is related to neutrophil penetration at sites of inflammation or injury. It has been shown with IL-8 blocking antibodies that IL-8 plays a role in tissue injury associated with neutrophils in case of acute inflammation (Harada et al., Molecular Medicine Today 2 , 482, 1996). Therefore, an inhibitor of IL-8 production may be useful for the treatment of diseases predominantly mediated by neutrophils, such as stroke and myocardial infarction, alone or after thrombolytic therapy, thermal injury, syndrome of respiratory distress in adults (ARDS), multiple organ injury after trauma, acute glomerulonephritis, dermatosis with acute inflammatory components, acute purulent meningitis or other disorders of the central nervous system, hemodialysis, leukopheresis, syndromes associated with granulocyte transfusion and enterocolitis necrotizing

The rhinovirus triggers the production of several pro-inflammatory cytokines, predominantly IL-8, which results in symptomatic diseases, for example acute rhinitis (Winther et al., Am. J. Rhinol. 12 , 17, 1998).

Other diseases triggered by IL-8 include myocardial ischemia and reperfusion, inflammatory bowel disease and many plus.

It is believed that IL-6 proinflammatory cytokine is involved in the acute phase response. IL-6 is a growth factor in a large number of cancer diseases, including multiple myeloma and related plasma cell dyscrasias (Treon, et al., Current Opinion in Hematology 5 , 42, 1998). It has also been found that it is an important mediator of inflammation within the central nervous system. Elevated levels of IL-6 have been found in various neurological disorders, including the AIDS dementia complex, Alzheimer's disease, multiple sclerosis, systemic lupus erythematosus, CNS plot and bacterial and viral meningitis (Gruol and col., Molecular Neurobiology 15 , 307, 1997). IL-6 also plays a significant role in osteoporosis. In murine models it has been shown that it causes bone resorption and induces osteoclast activity (Ershler et al., Development and Comparative Immunol. 21 , 487, 1997). There are " in vivo " marked differences in cytokines, for example in levels of IL-6, between osteoclasts of normal bones and those of bones of patients suffering from Paget's disease (Mills, et al., Calcif. Tissue Int. 61 , 16, 1997). It has been shown that a large number of cytokines are involved in cancerous cachexia. The severity of the key parameters of cachexia can be reduced by treatment with anti-IL-6 antibodies or with IL-6 receptor antagonists (Strassmann et al., Cytokins Mol. Ther. 1 , 107, 1995). Various infectious diseases, for example influenza, indicate that IL-6 and IFN-alpha are key factors in both symptom formation and host defense (Hayden, et al., J. Clin. Invest. 101 , 643, 1998). Overexpression of IL-6 also appears to be involved in the pathology of a large number of diseases, including multiple myeloma, rheumatoid arthritis, Castleman's disease, psoriasis and post-menopausal osteoporosis (Simpson et al., Protein Sci. 6 , 929, 1997). Compounds that interfere with the production of cytokines, including IL-6 and TNF, are effective in blocking passive cutaneous anaphylaxis in mice (Scholz et al., J. Med. Chem. 41 , 1050, 1998).

GM-CSF is another important pro-inflammatory cytokine in a large number of therapeutic diseases. It influences not only the proliferation and differentiation of geminal cells, but also regulates various additional cells that are involved in acute and chronic inflammation. Treatment with GM-CSF has been attempted in a large number of pathological conditions, including burn-wound healing, resolution of cutaneous grafts and cytostatic mucositis and radiation-induced mucositis (Masucci, Medical Oncology 13 , 149, nineteen ninety six). It also appears that GM-CSF plays a role in the replication of human immunodeficiency virus (HIV) in macrophage lineage cells with relevance in AIDS therapy (Crowe et al., Journal of Leukocyte Biology 62 , 41, 1997 ). Bronchial asthma is characterized by an inflammatory process in the lungs. The cytokines involved include GM-CSF, among others (Lee, JR Coll. Physicians Lond. 32 , 56, 1998).

It has been found that interferon? (IFN?) Is involved in a large number of diseases. It has been associated with increasing collagen deposition, which is a central histopathological feature of graft host disease (Parkman, Curr. Opin. Hematol. 5, 22, 1998). After a kidney transplant, a patient was diagnosed with acute myelogenous leukemia. Retrospective analysis of peripheral blood cytokines reveals elevated levels of GM-CSF and IFNγ. These elevated levels coincide with an increase in the number of leukocytes in the peripheral blood (Burke et al., Leuk. Lymphoma. 19 , 173, 1995). The development of insulin-dependent diabetes (type 1) may correlate with the accumulation of T cells, which produce IFNγ, in the islet cells of the pancreas (Ablumunits et al., J. Autoimmun. 11 , 73, 1998). IFNγ together with TNF, IL-2 and IL-6 lead to the activation of most peripheral T cells before the development of lesions of the central nervous system in the case of diseases of the multiple sclerosis type (MS ) and AIDS dementia complex (Martino et al., Ann. Neurol. 43 , 340, 1998). Atherosclerotic lesions manifest themselves in arterial diseases, which lead to heart and brain infarctions. In these lesions many activated immune cells are present, especially T cells and macrophages. These cells produce large amounts of proinflammatory cytokines, for example TNF, IL-1 and IFNγ. It is believed that these cytokines are involved in the promotion of apoptosis or cell death programs of surrounding vascular smooth muscle cells, which results in atherosclerotic lesions (Geng, Heart Vessels Suppl. 12 , 76, 1997). Allergic subjects produce IFNγ-specific mRNA after being treated with Vespula venom (Bonay et al., Clin. Exp. Immunol. 109 , 342, 1997). It has been shown that the expression of a large number of cytokines, influenced by IFNγ, increases after a delayed type hypersensitivity reaction, which indicates that IFNγ plays a role in atopic dermatitis (Szepietowski et al. , Br. J. Dermatol. 137 , 195, 1997). Histopathological and immunohistological studies have been performed in cases of fatal cerebral malaria. There are indications of high concentration of IFNγ among other cytokines, which indicates that it plays a role in this disease (Udomsangpetch et al., Am. J. Trop. Med. Hyg. 57 , 501, 1997). The importance of free radical species in the pathogenesis of various infectious diseases has already been recognized. The mechanism of nitric oxide synthesis is activated in response to infection with certain viruses by induction of proinflammatory cytokines, for example IFNγ (Akaike et al., Proc. Soc. Exp. Biol. Med. 217 , 64 , 1998). Patients, chronically infected with hepatitis B virus (HBV) can develop cirrhosis and hepatocellular carcinoma. The genetic expression of the virus and its replication in transgenic HBV rats can be suppressed with a post-transcriptional mechanism mediated by IFNγ, TNF and IL-2 (Chisari et al., Springer Semin. Immunopathol. 17 , 261, nineteen ninety five). IFNγ can selectively inhibit cytokine-induced bone resorption. It seems to do so with the intermediation of nitric oxide (NO), which is an important molecule that regulates bone remodeling. NO can intervene as a mediator of bone disease in the following cases: rheumatoid arthritis, osteolysis associated with tumors and postmenopausal osteoporosis (Evans et al., J. Bone Miner. Res. 11 , 300, 1996). Studies with genetically deficient mice have shown that IL-12-dependent IFN? Production is critical for early parasitic growth control. Although this process is independent of nitric oxide, chronic infection control appears to be dependent on NO (Alexander et al., Philos. Trans. R. Soc. Lond. B Biol. Sci. 352 , 1355, 1997). NO is an important vasodilator and there is convincing evidence of its role in cardiovascular shock (Kilbourn et al., Dis. Mon. 43 , 277, 1997). IFNγ is required for the progression of chronic intestinal inflammation, for example in Crohn's disease and inflammatory bowel disease (IBD) diseases, presumably with the intermediation of CD4 + lymphocytes, probably of the TH1 phenotype (Sartor, Aliment Pharmacol. Ther. 10 , Suppl. 2, 43, 1996). An elevated serum IgE level is associated with various atopic diseases, for example bronchial asthma and atopic dermatitis. The IFNγ level is negatively related to serum IgE, which
suggests that IFNγ plays a role in atopic patients (Teramoto et al., Clin. Exp. Allergy 28 , 74, 1998).

WO 01/01986 describes specific compounds, to which the ability to inhibit is attributed to TNF-alpha. Of certain compounds described in WO 01/01986 indicates that they are effective in treating diseases following: dementia associated with HIV infection, the glaucoma, optic neuropathy, optic neuritis, ischemia of retina, laser induced optical injury, the vitreous-proliferative retinopathy induced by surgery or trauma, cerebral ischemia, ischemia hypoxia, hypoglycemia, domoic acid poisoning, anoxia, carbon monoxide or manganese poisoning or cyanide, Huntington's disease, Alzheimer's disease, Parkinson's disease, meningitis, multiple sclerosis and other diseases of demyelination, lateral sclerosis amyotrophic, cranial or spinal trauma, the accesses, seizures, olivopontocerebellar atrophy, Neuropathic color syndromes, diabetic neuropathy, HIV-related neuropathy, the MERRF and MELAS syndromes, the Leber's disease, Wernicke's encephalopathy, the syndrome of Rett, homocysteinuria, hyperprolinemia, hyperhomocysteinemia, non-ketotic hyperglycinemia, hydroxybutyric aminoaciduria, deficiency of sulfite oxidase, the combined systemic disease, Saturnine encephalopathy, Touret's syndrome, encephalopathy liver, drug addiction, drug tolerance, drug dependence, depression, anxiety and schizophrenia.

The compounds, which modulate the release of a or more of the above inflammatory cytokines, may be useful to treat diseases associated with the release of these cytokines For example, WO 98/52558 describes heteroaryl urea compounds, which are indicated for the treatment of cytokine-mediated diseases. In WO 99/23091 describes another group of urea compounds that are useful as anti-inflammatory agents. In WO 99/32463, describe aryl ureas and its use to treat cytokine diseases and enzyme-mediated diseases proteolytic WO 00/41698 describes aryl-ureas that are said to be useful for treat diseases caused by p38 MAP kinase.

In US Pat. No. 5,162,360 describe urea compounds substituted by aryl on N and by heterocyclyl on N ', which are said to be useful for treat hypercholesterolemia and atherosclerosis.

The works cited above support the principle that the inhibition of cytokine production is beneficial for the treatment of diseases mediated by cytokines There is, therefore, demand for molecule inhibitors small to treat these diseases with efficacy and profiles Optimized pharmacokinetic and safety.

Brief Summary of the Invention

The works cited above support the principle that the inhibition of cytokine production is beneficial for the treatment of various disease states.

It is therefore an object of the invention the provide new urea compounds fused with benzo 1,4-disubstituted according to claim 1, which inhibit inflammatory cytokines, for example the interleukin-1 and tumor necrosis factor.

Another object of the invention is to provide methods to treat diseases and disease states mediated by cytokines, which carry inflammation, for example chronic inflammatory disease, using the new compounds of the invention.

Another object of the invention consists in provide processes for obtaining new compounds mentioned before.

Detailed description of the invention

one

3

4

5

6

7

8

9

10

and acids or salts pharmaceutically acceptable of the same.

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The following are preferred compounds of the invention:

eleven

12

13

14

or acids or salts pharmaceutically acceptable of the same.

In all the above compounds described in this request, if it happens that the nomenclature was in conflict with the structure represented, then it is given by assuming that the compound is defined by the structure.

The invention includes the use of any one of the compounds described above, which contain one or more atoms of asymmetric carbon and may be present in the form of racemates, of racemic mixtures, of individual enantiomers, of mixtures of diastereoisomers and individual diastereomers. All shapes Isomers of these compounds are expressly included in the present invention Each stereogenic carbon atom can have the R or S configuration, or a combination of configurations.

Some of the compounds present may exist in more than one tautomeric form. The invention includes the methods that employ any such tautomer.

All terms used in this description, unless otherwise indicated, should be taken in  its ordinary meaning, already known in the art. For example, "C 1-4 alkoxy" is an alkyl C 1-4 having a terminal oxygen, for example methoxy, ethoxy, propoxy, butoxy. It is understood that all alkyl, alkenyl and alkynyl groups have a straight chain or branched, if structurally possible and unless Specify something else. Other more specific definitions are the following:

The term "aroyl" used herein description should be understood in the meaning of "benzoyl" or "naphthoyl."

The term "carbocycle" should be understood in the meaning of a hydrocarbon residue that contains three to twelve carbon atoms Carbocycles include rings carbonates containing three to ten carbon atoms. These carbocycles can be aromatic ring systems or not aromatic Non-aromatic ring systems may be mono- or polyunsaturated. Preferred carbocycles include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl, cycloheptenyl, phenyl, indanyl, indenyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl, decahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl. Certain terms of cycloalkyl, for example cyclobutanyl and cyclobutyl can be used interchangeably.

The term "heterocycle" indicates a moiety stable, monocyclic 4-8 non-aromatic heterocycle links (but preferably 5 or 6 links) or bicyclic of 8-11 links, which can be saturated or unsaturated. Each heterocycle consists of carbon atoms and one or more, with preference of 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulfur. The heterocycle can be linked through any atom of the cycle, which results in the generation of a structure stable. Unless otherwise indicated, heterocycles include but are not limited to: for example oxetanil, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylenesulfonyl, tetramethylenesulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl, dithianyl or 2-oxa- or 2-tia-5-aza-bicyclo [2.2.1] heptanyl.

The term "heteroaryl" should be understood in the meaning of a monocyclic aromatic ring of 5-8 links or bicyclic of 8-11 links, containing 1-4 heteroatoms, per example N, O and S. Unless otherwise indicated, the heteroaryls include: pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzopyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzooxazolonyl, benzo [1,4] oxazin-3-onyl, benzodioxolyl, benzo [1,3] dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl.

The term "heteroatom" as used here it must be understood in the meaning of atoms other than carbon, for example O, N, S and P.

In all alkyl groups or chains carbonates, in which one or more carbon atoms have optionally replaced by heteroatoms: O, S or N, is given by assuming that if N is not substituted, then it is NH; is given by further assuming that heteroatoms can replace atoms of carbon terminals or to the internal carbon atoms of a linear or branched carbon chain. Such groups can be substituted in the manner described above by groups such as oxo, to form remnants of the following definitions, but without limited to them: alkoxycarbonyl, acyl, amido and thioxo.

The term "aryl" as used herein should be taken in the meaning of aromatic carbocycle or of heteroaryl, already defined before. Unless specified by another Thus, each aryl or heteroaryl includes its total derivatives or partially hydrogenated. For example, quinolinyl may include to decahydroquinolinyl and tetrahydroquinolinyl; naphthyl it can include its derivatives, such as tetrahydronaphthyl. Other wholly or partially hydrogenated derivatives of the compounds aryl and heteroaryl described herein will be apparent to the Organic chemistry experts.

The terms that are analogous to the remains previous cyclics, for example aryloxy or heteroaryl-amine, should be understood in the meaning of aryl, heteroaryl, heterocycle, defined above, joined to their corresponding group.

As used herein, "nitrogen" and "sulfur" includes all oxidized forms of nitrogen and sulfur and quaternary forms of any basic nitrogen. By example, in the case of an -S-alkyl moiety C_ {1-6}, unless otherwise indicated, is it assumes that this includes the remains -S (O) -C 1-6 alkyl and -S (O) 2 -alkyl C_ {1-6}.

The term "halogen" as used in This description should be understood in the meaning of bromine, chlorine, fluorine or iodine. The definitions "totally or partially halogenated "," substituted by one or more halogen atoms " include for example mono-, di- or derivatives tri-halogenated of one or more carbon atoms. In the case of alkyl, a non-limiting example would be -CH 2 CHF 2, -CF 3, etc.

The compounds of the invention are only those who consider themselves "chemically stable", in the opinion of the experts in organic chemistry. For example, a compound that have a "floating valence" or a "carbanión" are not compounds contemplated in the methods of the invention which are described in this application.

The invention includes derivatives Pharmaceutically acceptable compounds present. A "pharmaceutically acceptable derivative" indicates any salt or pharmaceutically acceptable ester or any other compound that, After administration to a patient, be able to regenerate (directly or indirectly) a useful compound of the invention, or a pharmacologically active metabolite or a pharmacologically active moiety active of the same. A pharmacologically active metabolite should understood in the meaning of any compound of the invention that is able to metabolize enzymatically or chemically. This includes, for example, hydroxylated derivative compounds or rusty of them.

Pharmaceutically acceptable salts include to those derived from acids and bases, organic and inorganic, pharmaceutically acceptable. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric acids, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, p-toluene-sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic. In obtaining the salts can be used other acids, for example oxalic acid, despite not being pharmaceutically acceptable in themselves, such salts are useful as intermediate compounds for obtaining the compounds present and their acid addition salts pharmaceutically acceptable. Salts derived from the appropriate bases include a alkali metal salts (eg sodium), of metals alkaline earth metals (eg magnesium), ammonium salts and salts of N- (C 1-4 alkyl) 4 +.

The scope of the invention is included in use of prodrugs of the present compounds. The prodrugs include those compounds that, after a transformation Simple chemistry, are modified to obtain the compounds of the invention. Simple chemical transformations include the hydrolysis, oxidation and reduction. Specifically, when administer a prodrug to a patient, the prodrug should transform into a compound defined before, with which you can display the desired pharmacological effect.

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Methods of use

According to the invention, new ones are provided. methods of use of the present compounds. The compounds here described effectively block cytokine production inflammatory cells. Inhibition of the production of cytokines is an attractive means to prevent and treat a large variety of diseases or disease conditions mediated by cytokines, associated with excess cytokine production, e.g. ex. diseases and pathological conditions that lead to inflammation. These compounds are therefore useful for the treatment of following disease states and diseases: osteoarthritis, atherosclerosis, contact dermatitis, diseases of bone resorption, reperfusion injury, asthma, sclerosis multiple, Guillain-Barre syndrome, the Crohn's disease, ulcerative colitis, psoriasis, graft host disease, systemic lupus erythematosus and insulin dependent diabetes mellitus, the rheumatoid arthritis, toxic shock syndrome, disease Alzheimer's, toxic shock syndrome, diabetes, inflammatory bowel disease, acute and chronic pain as well such as inflammation symptoms and cardiovascular disease, the stroke, myocardial infarction, alone or as a result of a thrombolytic therapy, thermal injury, distress syndrome Respiratory adult (ARDS), multiple organ injury to Trauma root, acute glomerulonephritis, dermatoses with acute inflammatory components, acute purulent meningitis or other disorders of the central nervous system, syndromes associated with hemodialysis, leukopheresis, syndromes associated with granulocyte transfusion and enterocolitis necrotizing

The compounds are useful for treating: complications that include restenosis arising from a percutaneous transluminal coronary angioplasty, arthritis traumatic, sepsis, chronic obstructive pulmonary disease and congestive heart failure

For therapeutic use, the compounds may administered in any conventional dosage form and in Any conventional mode. The routes of administration include, but they are not limited to: intravenous, intramuscular, subcutaneous, intrasynovial and infusion, sublingual, transdermal, oral, topical or by inhalation. Preferred modes of administration are oral. and intravenous.

The compounds can be administered alone or in combination with adjuvants to improve the stability of inhibitors, facilitate the administration of the compositions pharmaceuticals that contain them in certain forms of execution, provide better dissolution or dispersion, increase the inhibitory activity, provide adjunctive therapy and the like, including other active ingredients. Advantageously, such combination therapies use lower doses of agents conventional therapies, thus avoiding the possible toxicity and adverse side effects that arise when Such agents are used in monotherapies. The compounds just described can be physically combined with therapeutic agents conventional or with other adjuvants within the same pharmaceutical composition Reference is made in this regard to Cappola et al., patent application US-09 / 902,822, PCT / US-01/21860 and provisional application US-60 / 313,527, each of them is incorporated into the present in its entirety as a reference. Advantageously, the Compounds can be administered in a single dosage form. In some embodiments, the pharmaceutical compositions that contain such combinations of compounds contain at least 5%, but preferably at least 20% of a compound present (w / w) or a combination thereof. The optimal percentage (w / w) of a compound of the invention may vary and be located within the range that those skilled in the art already know. How alternatively, the compounds can be administered separately (already either in series, or in parallel). The separate dosage allows A more flexible regime.

As mentioned before, the ways of Dosage of the compounds described herein include vehicles and pharmaceutically acceptable adjuvants, already known from the subject matter experts. These vehicles and adjuvants include, by example, ion exchangers, alumina, stearate aluminum, lecithin, whey proteins, substances buffer, water, salts or electrolytes and substances based on cellulose. Preferred dosage forms include tablets, capsules, pills, liquids, the solutions, the suspensions, the emulsions, the pills, the syrups, reconstitutable powders, granules, suppositories and transdermal patches. The methods for manufacture of such dosage forms are already known (see, for example H.C. Ansel and N.G. Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea and Febiger, 1990). Dosage levels and requirements are fine. recognized in the art and those skilled in the art may choose by applying available techniques and methods, suitable for the concrete patient In some forms of execution, the levels of Dosage is between 1 and 1000 mg / dose for a patient of 70 kg weight

Although one dose per day may be sufficient, Up to 5 doses per day may be administered. In the case of dose oral, up to 2000 mg / day may be necessary. In this regard it refers to the provisional patent application US-60 / 339,249. Those skilled in the art may appreciate that depending on specific factors may be necessary a dosage less than or greater than indicated. For example, the concrete dosage and treatment regimen will depend on factors such as the patient's general health status, the severity and the course of the disorder suffered by the patient or the predisposition you have to acquire it and also the criterion of optional attending to the patient.

Synthesis methods

The present compounds can be obtained by methods described in US Pat. No. 6,319,921, which is incorporates herein by reference, by methods that describe below or are already known in the art. The compounds intermediates used to obtain the compounds of the invention are commercial products or compounds that can easily obtained by methods that those skilled in the art already They know In this regard, it also refers to requests for US-09 / 505,582, 09 / 484,638, 09 / 714,539, 09 / 611,109, 09 / 698,442 and provisional patent applications US-60 / 216,283, 60 / 283,642, 60 / 291,425, 60 / 293,600 and 60 / 295,909, which are incorporated herein in its entirety as references.

The optimal conditions and times of reaction may vary depending on the specific reagents that are employ. Unless otherwise indicated, experts in the matter can easily choose solvents, temperatures and Other reaction conditions. For example, the progress of the reaction can be followed with a layer chromatography analysis fine (CCF), if desired, and intermediate compounds and products they can be purified by chromatography through silica gel and / or recrystallization

Morpholine Intermediates substituted, which are used to obtain the compounds according to  claim 1, are easily obtained by methods already known in the art or are commercial products, as indicated in the following table 1.

TABLE 1

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16

17

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Example 1 Synthesis of the 1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) naphthalen-1-yl] -urea

18

A mixture is heated at 80 ° C for 3 hours. of the 4-N-Boc-amino-1-naphthol (0.444 g), hydrochloride 4- (2-Chloroethyl) morpholine (0.3435 g) and Potassium carbonate powder (0.93 g) in acetonitrile (15 ml), se cooled to room temperature and diluted with ethyl acetate and Water. The organic phase is washed with water, brine, dried (MgSO4) and volatile components are removed under vacuum. By purification of the residue by flash chromatography using as eluent 12% hexane in ethyl acetate and concentration with vacuum of the product rich fractions the ether of 4-N-Boc-aminonaphthyl wanted.

Stir at room temperature for 20 hours. a solution of the previous ether of 4-N-Boc-aminonaphthyl (0.511 g) and HCl (1 ml of a 4 M solution in dioxane) in 5 ml dioxane By removing volatile components with vacuum, Obtain the desired 4-aminonaphthyl ether. To one solution of 5-amino-3-t-butyl-1- (4-methylphenyl) pyrazole  (0.15 g), a saturated solution of NaHCO 3 (15 ml) and dichloromethane (15 ml) is added at 0 ° C phosgene (1.17 ml, 1.93 M in toluene). The mixture is stirred for 15 minutes, the phase is dried organic (MgSO4) and volatile components are removed with empty. The residue is added to a solution of the above ether of 4-aminonaphthyl (0.15 g) and diisopropylethyl amine (0.32 ml) in 10 ml of THF and Stir the mixture overnight. Ethyl acetate is added and water, the organic phase is washed with water, brine and dried (MgSO 4). By eliminating volatile components with vacuum, purification of the residue by flash chromatography using ethyl acetate as eluent, concentration in vacuo of the product rich fractions and subsequent recrystallization in hexanes and ethyl acetate the epigraph compound is obtained.

The following compounds can be obtained according to the procedure described in the previous example using the appropriate morpholine intermediate compound of Table 1. Applying the procedure described by T. Watanabe et al. (Chem. Pharm. Bull. 45 , 996, 1997), treating the morpholine analogue of table 1 with chloroacetaldehyde in water, acetic acid and methylene chloride in the presence of desired sodium triacetoxyborohydride, which obtains the desired intermediate chloroethylmorpholine compound, which is obtained used for synthesis.

acid methylamide 4- (2- {4- [3- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -morpholine-2- carboxylic;

methyl acid phenylamide 4- (2-4- [3- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -carboxylic;

acid dimethylamide 4- (2- {4- [3- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -morpholine-2- carboxylic;

acid phenylamide 4- (2- {4- [3- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -morpholine-2- carboxylic;

2- [4- (2- {4- [3- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} ethyl) -morpholin- 2-yl] -N, N-dimethyl-acetamide;

1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- {4- [2- (2-phenyl-morpholin-4-yl) -ethoxy] -naphthalen-1 -il} -urea;

1- {4- [2- (2-Benzyl-morpholin-4-yl) -ethoxy] -naphthalen-1-yl} -3- (5-tert-butyl-2-p-tolyl-2H-pyrazole-3 -il) -urea;

1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- {4- [2- (2-phenethyl-morpholin-4-yl) -ethoxy] -naphthalen-1 -il} -urea;

1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- {4- [2- (2-phenoxymethyl-morpholin-4-yl) -ethoxy] -naphthalen-1 -il} -urea;

1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- (4- {2- [2- (1-phenyl-ethyl) -morpholin-4-yl] - ethoxy} -naphthalen-1-yl) -urea;

1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- {4- [2- (2-oxa-5-aza-bicyclo [2.2.1] hept-5 -yl) -ethoxy] -naphthalen-1-yl} -urea;

1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- {4- [2- (2-thiazol-2-yl-morpholin-4-yl) -ethoxy] -naftalen-1-yl} -urea;

1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- {4- [2- (2,3-dihydro-benzo [1,4] oxazin-4-yl ) -ethoxy] -naphthalen-1-yl} -urea.

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Example 2 Synthesis of the 1- [5-tert-butyl-2- (2-methylpyridin-5-yl) -2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-yl-ethoxy) naphthalen-1- il] -urea

19

Slowly heat a suspension of 90 ° C diethyl malonate (42 ml) and sodium (4.71 g), stirred at 90 ° C for 2 hours and at 120 ° C for 30 minutes, then cooled to room temperature. Toluene (200 ml) is added and 2-chloro-5-nitropyridine (25.0 g) and the mixture is heated at 110 ° C for 1.5 hours and stir at room temperature for 17 h. After removing the Volatile components under vacuum 6N HCl (200 ml) is added, heat the mixture at reflux for 4 h and cool to temperature ambient. The solution is neutralized with solid sodium carbonate, extracted with ethyl acetate (6x100 ml), dried with sodium sulfate solid and concentrated, obtaining a dark solid. It is purified this material by flash chromatography using as eluent 20% ethyl acetate in petroleum ether. By concentration with vacuum of the product rich fractions the 2-methyl-5-nitropyridine. A mixture of the 2-methyl-5-nitropyridine (13.0 g) and 10% Pd in activated carbon (0.1 g) in 1,4-dioxane (150 ml) with a hydrogen pressure of 50 psi for 24 hours and seeps through the ground of diatoms By removal of volatile components with vacuum you get the 5-amino-2-methylpyridine. A solution of 5-amino-2-methylpyridine (9.90 g) in 6 N HCl (100 ml), cooled to 0 ° C and stirred vigorously throughout the procedure. Sodium nitrite is added  (6.32 g) in water (50 ml). After 30 minutes, add chloride tin (II) dihydrate (52.0 g) in 6 N HCl (100 ml) and the mixture is stirred reactant suspension at 0 ° C for 3 hours. The pH is adjusted to 14 with a 40% aqueous solution of potassium hydroxide and extracted with ethyl acetate. The organic extracts are combined, dried (MgSO4) and by elimination of volatile components with empty you get the 5-hydrazino-2-methylpyridine.  A solution is boiled at reflux for 17 hours. from 5-hydrazino-2-methylpyridine (8.0 g) and 4,4-dimethyl-3-oxopentanonitrile (10.0 g) in ethanol (200 ml) and 6 N HCl (6 ml) and cooled to room temperature. Solid sodium hydrogen carbonate is added to neutralize the solution. The suspension is filtered and by removal of volatile components with vacuum you get a residue, which is purified by column chromatography using as eluent ethyl acetate. By concentration with vacuum of the product rich fractions you get the 5-amino-3-t-butyl-1- (2-methylpyridin-5-yl) pyrazole. To a mixture of compound 3 (0.40 g) in dichloromethane (20 ml) and a saturated aqueous solution of sodium bicarbonate (20 ml) cooled at 0 ° C phosgene (1.93 M in toluene, 1.50 ml) is added. Stir the mixture for 15 min, the organic phase is dried (MgSO4) and dried Eliminates most volatile components with vacuum. Be add a solution of the intermediate ether compound of 4-aminonaphthyl of example 1 (0.30 g) in dichloromethane (10 ml) and the mixture is stirred at room temperature for 17 hours By eliminating volatile components with A residue is obtained under vacuum, which is purified by chromatography of column using 10% methanol in ethyl acetate as eluent. By vacuum concentration of the product rich fractions and recrystallization from a hot tetrahydrofuran / ether mixture of oil is obtained the epigraph compound.

The following compounds can be obtained according to the procedure described in the previous example using the appropriate morpholine intermediate compound of Table 1. Applying the procedure described by T. Watanabe et al. (Chem. Pharm. Bull. 45 , 996, 1997), treating the morpholine analogue of table 1 with chloroacetaldehyde in water, acetic acid and methylene chloride in the presence of sodium triacetoxyborohydride gives the desired intermediate compound of chloroethylmorpholine which is used In the synthesis.

4- [2- (4- {3- [5-tert-Butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -ureido} naphthalen-1- acid methylamide iloxy) -
ethyl] -morpholine-2-carboxylic;

methyl phenyl amide of the acid 4- {3- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -ureido} -naphthalen-1-yloxy) -ethyl] -morpholine- 2-carboxylic;

acid dimethylamide 4- [2- (4- {3- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -ureido} -naphthalen-1-yloxy) -ethyl] -morpholine-2-carboxylic;

4- [2- (4- {3- [5-tert-Butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -ureido} -naphthalen-1 acid phenylamide -yloxy) -
ethyl] -morpholine-2-carboxylic;

2-4- [2- (4- {3- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -ureido} -naphthalen-1- yloxy) -ethyl] -morpholin-2-yl} -N,
N-dimethyl acetamide;

1- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- {4- [2- (2-phenyl-morpholin-4-yl ) -ethoxy] -naphthalen-1-yl} -urea;

1- {4- [2- (2-Benzyl-morpholin-4-yl) -ethoxy] -naphthalen-1-yl} -3- [5-tert-butyl-2- (6-methyl-pyridin-3- il) -2H-pyrazol-3-yl] -urea;

1- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- {4- [2- (2-phenethyl-morpholin-4-yl ) -ethoxy] -naphthalen-1-yl} -urea;

1- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- {4- [2- (2-phenoxymethyl-morpholin-4-yl ) -ethoxy] -naphthalen-1-yl} -urea;

1- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- (4- {2- [2- (1-phenyl-ethyl) -morpholin-4-yl] -ethoxy} -naphthalen-1-
il) -urea;

1- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- {4- [2- (2-oxa-5-aza-bike) [2.2.1] hept-5-yl) -ethoxy] -naphthalen-1-yl} -urea;

1- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3-14- [2- (2-thiazol-2-yl-morpholin) 4-yl) -ethoxy] -naphthalen-1-yl} -urea;

acid methylamide 4- (2- {4- [3- (5-tert-butyl-2- (6-methoxypyridin-3-yl) -2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl ) -morpholine-2-carboxylic;

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4- (2- {4- [3- (5-tert-Butyl-2- (6-methoxypyridin-3-yl) -2H-pyrazol-3-yl) -ureido] naphthalen- acid methyl-phenyl-amide one-
yloxy} -ethyl) -morpholine-2-carboxylic;

4- (2-4- [3- (5-tert-Butyl-2- (6-methoxypyridin-3-yl) -2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} methylamide -
ethyl) -morpholine-2-carboxylic;

4- (2- {4- [3- (5-tert-Butyl-2- (6-methoxypyridin-3-yl) -2H-pyrazol-3-yl) -ureido] -naphthalen-1 acid methyl-phenylamide -
yloxy} -ethyl) -morpholine-2-carboxylic;

acid dimethylamide 4- (2- {4- [3- (5-tert-butyl-2- (6-methoxypyridin-3-yl) -2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl ) -morpholine-2-carboxylic;

acid phenylamide 4- (2- {4- [3- (5-tert-butyl-2- (6-methoxypyridin-3-yl) -2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl ) -morpholine-2-carboxylic;

2- [4- (2- {4- [3- (5-tert-butyl-2- (6-methoxypyridin-3-yl) -2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy } -ethyl) -morpholin-2-yl] -N, N-dimethyl-acetamide;

1- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- {4- [2- (2,3-dihydrobenzo [1,4 ] oxazin-4-yl) -ethoxy] -naphtha-
len-1-il} -urea.

The following compound can be obtained by applying the same procedure described, but using the 5-amino-3-t-butyl-1- (2-methoxypyridin-5-yl) pyrazole instead of 5-amino-3-t-butyl-1- (2-methylpyridin-5-yl) pyrazole:

1- (5-tert-butyl-2- (6-methoxypyridin-3-yl) -2H-pyrazol-3-yl) -3- {4- [2- (2-oxa-5-aza-bicyclo [2.2 .1] hept-5-yl) -ethoxy] -naphthalen-1-yl} -urea.

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Example 3 Obtaining the 1- [5-tert-butyl-2-methyl-2H-pyrazol-3-yl] -3-4- (2-morpholin-4-yl-ethoxy) naphthalen-1-yl] -urea

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To a mixture of the intermediate ether compound of 4-aminonaphthyl of example 1 (0.40 g) in dichloromethane (35 ml) and a saturated aqueous solution of bicarbonate sodium (35 ml) is added at 0 ° C phosgene (1.93 M in toluene, 1.5 ml) The mixture is stirred for 15 minutes, the organic phase is dried (MgSO4) and most of the components are removed Volatile with vacuum. A solution of the 5-amino-3-tert-butyl-1-methylpyrazole  (0.20 g) in dichloromethane and the mixture is stirred at temperature atmosphere for 17 hours. By component removal volatile under vacuum a residue is obtained which is purified by column chromatography, using 10% methanol as eluent in ethyl acetate. By concentration with vacuum of the fractions rich in product and recrystallization from hot ethyl acetate the epigraph compound is obtained.

The following compounds can be obtained according to the procedure described in the previous example using the appropriate morpholine intermediate compound of Table 1. Applying the procedure described by T. Watanabe et al. (Chem. Pharm Bull. 45 , 996, 1997) and by treating the morpholine analogue of Table 1 with chloroacetaldehyde in water, acetic acid and methylene chloride in the presence of desired sodium triacetoxyborohydride, the desired chloroethylmorpholine intermediate compound is obtained, which is used for the synthesis

acid methylamide 4-2- {4- [3- (5-tert-Butyl-2-methyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} ethyl) -morpholine-2-carboxylic acid;

methyl phenyl amide of the acid 4- (2- {4- [3- (5-tert-Butyl-2-methyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -morpholine-2-carboxylic acid;

acid methylamide 4- (2- {4- [3- (5-tert-Butyl-2-methyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -morpholine-2-carboxylic acid;

methyl acid phenylamide 4-2- {4- [3- (5-tert-Butyl-2-methyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} ethyl) -morpholine-2-carboxylic acid;

acid dimethylamide 4-2- {4- [3- (5-tert-Butyl-2-methyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} ethyl) -morpholine-2-carboxylic acid;

acid phenylamide 4-2- {4- [3- (5-tert-Butyl-2-methyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -morpholine-2-carboxylic acid;

2- [4- (2- {4- [3- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -morpholin-2 -yl] -N, N-dimethyl-acetamide;

1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- {4- [2- (2-phenyl-morpholin-4-yl) -ethoxy] -naphthalen-1-yl }-urea;

1- {4- [2- (2-Benzyl-morpholin-4-yl) -ethoxy] -naphthalen-1-yl} -3- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl )-urea;

1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- {4- [2- (2-phenethyl-morpholin-4-yl) -ethoxy] -naphthalen-1-yl }-urea;

1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- {4- [2- (2-phenoxymethyl-morpholin-4-yl) -ethoxy] -naphthalen-1-yl }-urea;

1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- (4- {2- [2- (1-phenyl-ethyl) -morpholin-4-yl] -ethoxy} -naftalen-1-yl) -urea;

1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- {4- [2- (2-thiazol-2-yl-morpholin-4-yl) -ethoxy] -naphthalen -1-yl} -urea;

1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- {4- [2- (2,3-dihydro-benzo [1,4] oxazin-4-yl) - ethoxy] -naphthalen-1-yl} -urea;

1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- {4- [2- (2-oxa-5-aza-bicyclo [2.2.1] hept-5-il ) -ethoxy] -naphthalen-1-yl} -urea;

1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- {4- [2- (2-thiazol-2-yl-morpholin-4-yl) -ethoxy] -naphthalen -1-yl} -urea;

1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- {4- [2- (2,3-dihydro-benzo [1,4] oxazin-4-yl) - ethoxy] -naphthalen-1-yl} -urea.

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Example 4 Synthesis of the 1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- {4- [2- (cyclopropylmethyl-amino) -pyrimidin-4-yloxy] -naphthalen-1-yl} - urea

twenty-one

The hydrochloride of the 4-amino-1-naphthol (3.65 g, 16.8 mmol, 1.0 equiv.) In 25 ml of anhydrous DMSO, then it is treated with potassium tert-butoxide (3.77 g, 33.6 mmol, 2.0 equiv.) and stir at room temperature for 30 min. Then, by means of a cannula, this solution is added to a 2,4-dichloropyrimidine solution (2.5 g, 16.8 mmol, 1.0 equiv.) in 10 ml of anhydrous DMSO. The mixture is heated resulting reactant in an oil bath at 70 ° C and stirred for 2.5 h. The reaction mixture is cooled and partitioned between EtOAc and water. The phases are separated and the aqueous phase is extracted two times with EtOAc. The organic fractions are combined, washed with water and brine, then dried (Na2SO4), filtered and solvents are removed under vacuum. The ether is purified from aminonaphthyl-chloropyrimidyl by chromatography of column through silica gel, obtaining 4.1 g (90%).

In a sealed tube the previous ether is mixed of aminonaphthyl-chloropyrimidyl (600 mg, 2.2 mmol), cyclopropanomethylamine (0.19 ml, 2.2 mmol) and triethylamine (0.31 ml, 2.2 mmol) in 5 ml of anhydrous THF. The mixture is placed in a oil bath at 70 ° C and stir overnight. The Reactant mixture and partition between EtOAc and water. They are separated phases and the eleven aqueous phase is extracted with EtOAc. They meet the organic fractions, washed with brine, dried (Na 2 SO 4), filter and solvents are removed with empty. The product is purified by column chromatography a through silica gel, obtaining 337 mg (50%) of the ether of desired cyclopropylmethylaminopyrimidine.

It dissolves on 3-amino-5-tert-butyl-2-methyl-2H-pyrazole (80 mg, 0.522 mmol, 1.0 equiv.) In 2.0 ml methylene chloride and 2.0 ml of a saturated aqueous solution of NaHCO3 is added. The biphasic mixture is cooled to 0 ° C, the organic phase is treated with phosgene in an added portion by syringe without shaking (0.91 ml of a 20% solution in toluene, 1.83 mmol, 3.5 equiv.). The resulting mixture is vigorously stirred at 0 ° C for 1 hour. The organic phase is separated, dried (Na2SO4) and dried filter Methylene chloride is removed under vacuum and the isocyanate in toluene with a solution of the above ether of cyclopropylmethylaminopyrimidine (160 mg, 0.522 mmol, 1.0 equiv.) in 4.0 ml of anhydrous THF. The mixture is stirred at room temperature. overnight, then the solvent is removed in vacuo. Be Purify the urea product by column chromatography through silica gel using 20 to 65% EtOAc as eluent in hexanes, then recrystallized from ether, obtaining 40 mg (16%) of the epigraph compound.

Example 5 Synthesis of the 1- [5-tert-butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-yl) -3- {4- [2- (cyclopropylmethyl-amino) -pyrimidin-4-yloxy] -naftalen-1-il} -urea

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In a sealed tube the diphenylphosphoryl azide (DPPA) (0.09 ml, 0.423 mmol, 1.1 equiv.) And triethylamine (0.075 ml, 0.54 mmol, 1.4 equiv.) to acid 5-tert-butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-carboxylic  (100 mg, 0.384 mmol, 1.0 equiv.) In 2.0 ml of dimethoxyethane anhydrous. The reaction mixture is heated at 85 ° C for 2.5 h, then a solution of the intermediate ether compound of cyclopropylmethylaminopyrimidine (see example 4) (118 mg, 0.38 mmol, 1.0 equiv.) in 3.0 ml of anhydrous THF and the mixture is stirred resulting at room temperature overnight. The solvent in vacuo and the crude urea is purified by column chromatography through silica gel using as eluent mixture 0 to 65% EtOAc in hexanes. It continues to purify the product by prep HPLC, obtaining 15 mg of the compound epigraphy (yield = 7%).

Example 6 Synthesis of the 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- {4- [2- (cyclopropylmethyl-amino) -pyrimidin-4-yloxy] -naphthalen-1-yl }-urea

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2. 3

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It dissolves on 3-amino-5-tert-butyl-2- (p-tolyl) -2H-pyrazole (2.39 g, 9.00 mmol, 1 equiv.) In 35 ml of methylene chloride and 35 ml of a saturated aqueous solution of NaHCO3 is added. The biphasic mixture is stirred until all solids have been completely dissolved and then cooled to 0 ° C. Phase is treated organic with phosgene in one portion using a syringe, but without stirring (15.8 ml of a 20% solution in toluene, 31.5 mmol, 3.5 equiv.). The resulting mixture is vigorously stirred at 0 ° C. for 1 h. The organic phase is separated, dried (Na2SO4) and it filters. Methylene chloride is removed under vacuum and treated the resulting isocyanate in toluene with a solution of the compound intermediate aminonaphthylchloropyrimidyl ether (see example 4) (2.45 g, 9.0 mmol, 1.0 equiv.) in 40 ml of anhydrous THF. Stir the mixture at room temperature for 3.5 h, then the solvent with vacuum. The residue is purified by chromatography of column through silica gel using eluent mixture 0 to 10% MeOH in methylene chloride, then recrystallized in ether, obtaining 1.90 g (40%) of the intermediate compound urea.

In a sealed tube the cyclopropanomethylamine (0.012 ml, 0.13 mmol), triethylamine (0.019 ml, 0.13 mmol) and the previous urea intermediate (70 mg, 0.13 mmol) and 1.5 ml of anhydrous THF. The mixture is heated in an oil bath at 70 ° C for 12 h. The solvent is removed with vacuum and the residue is purified by column chromatography a through silica gel using eluent MeOH from 0 to 10% in methylene chloride. By preparatory HPLC in reverse phase 11 mg of the epigraphy compound are obtained (yield = 15%).

Example 7 Synthesis of the 1- (5-tert-butyl-2-methyl-2 pyrazol-3-yl) -3- {4- [2- (cyclopropylmethyl-amino) -6-methyl-pyrimidin-4-yloxy] -naphthalen-1-yl} -urea

24

The hydrochloride of the 4-amino-1-naphthol (4.00 g, 18.4 mmol, 1.0 equiv.) In 25 ml of anhydrous DMSO, is Treat with potassium tert-butoxide (4.13 g, 36.8 mmol, 2.0 equiv.) and stir at room temperature for 30 min. With a syringe this solution is added on a solution of the 2,4-dichloro-6-methyl-pyrimidine  (3.00 g, 18.4 mmol, 1.0 equiv.) In 10 ml of anhydrous DMSO. Be heat the resulting reaction mixture in an oil bath to 70 ° C and stir for 2.5 h. The reaction mixture is cooled and partition between EtOAc and water. The phases are separated and the aqueous phase twice with EtOAc. The fractions meet organic, washed with water and brine, then dried (Na 2 SO 4), filter and solvents are removed with empty. The 4-aminonaphthyloxy-2-chloro-6-methylpyrimidine by column chromatography through silica gel using as eluent mixture 0 to 60% EtOAc in hexanes, obtaining 4.68 g (89%).

In a sealed tube the 4-aminonaphthyloxy-2-chloro-6-methylpyrimidine (1.00 g, 3.5 mmol), cyclopropanomethylamine (0.30 ml, 3.5 mmol) and triethylamine (0.49 ml, 3.5 mmol) in 10 ml of anhydrous THF. Be place the mixture in an oil bath at 70 ° C and stir for one night. The reaction mixture is cooled and partitioned between EtOAc and water. The phases are separated and the aqueous phase is extracted a Once with EtOAc. The organic fractions are combined, washed with brine, then dried (Na2SO4), filtered and dried remove solvents with vacuum. The product is purified by column chromatography through silica gel using as eluent mixture MeOH from 0 to 10% in methylene chloride, of this so 504 mg (45%) of the ether of desired cyclopropylmethylaminopyrimidine.

It dissolves on 3-amino-5-tert-butyl-2-methyl-2H-pyrazole (90 mg, 0.59 mmol, 1.0 equiv.) In 2.0 ml methylene chloride and 2.0 ml of a saturated aqueous solution of NaHCO3 is added. Be cool the biphasic mixture to 0 ° C, then the organic phase is treated with phosgene in one portion by syringe without shaking (1.03  ml of a 20% solution in toluene, 2.06 mmol, 3-5 equiv.). Be vigorously stir the resulting mixture at 0 ° C for 1 h. Be Separate the organic phase, dry (Na2SO4) and filter. Be Remove methylene chloride in vacuo and isocyanate is treated in toluene with a solution of the above intermediate ether compound cyclopropylmethylaminopyrimidine (189 mg, 0.59 mmol, 1.0 equiv.) in 4.0 ml of anhydrous THF. The mixture is stirred at room temperature. overnight, then the solvent is removed in vacuo. Be Purify the urea product by column chromatography through silica gel using 20 to 65% EtOAc in hexanes, then recrystallize from ether, obtaining 165 mg (56%) of the compound epigraph

Example 8 Synthesis of the 1- [5-tert-butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-yl) -3- {4-12- (cyclopropylmethyl-amino) -6-methyl-pyrimidin-4 -yloxy] -naphthalen-1-yl} -urea

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25

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5-tert-Butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-carboxylic acid (100 mg, 0.38 mmol, 1)
equiv.), DPPA (0.12 ml, 0.57 mmol, 1.5 equiv.) and triethylamine (0.09 ml, 0.65 mmol, 1.7 equiv.) in 5.0 ml of benzene and Stir the reaction mixture at room temperature for 5 h. The resulting homogeneous solution is transferred to a separatory funnel and washed twice with 10 ml of a saturated aqueous solution of NaHCO3. It is further washed once with brine, dried (MgSO4), filtered and transferred to a sealed tube in the presence of the naphthylamine intermediate (123 mg, 0.38 mmol, 1.0 equiv.). Some benzene and methylene chloride (\1 ml of each) are added to facilitate dissolution of the reagents. The sealed tube is placed in an oil bath at 90 ° C and stirred for 12 h. After cooling, the solvents are removed in vacuo and the crude material is purified by column chromatography through silica gel using the EtOAc in hexanes as eluent mixture. Recrystallization from acetonitrile gives 142 mg of the epigraphy compound as a white solid.

Example 9 Synthesis of the 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- (4- {2 - [(tetrahydro-furan-2-ylmethyl) -amino] -pyrimidin-4- yloxy} -naphthalen-1-yl) -urea (two enantiomers)

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26

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The compound is dissolved in a sealed tube intermediate aminonaphthylchloropyrimidyl ether (see example 4) (338 mg, 1.24 mmol, 1.0 equiv.) in 3.5 ml of THF anhydrous and treated with triethylamine (0.18 ml, 1.30 mmol) and (S) -tetrahydrofurfurylamine (0.13 ml, 1.24 mmol). The mixture is heated at 75 ° C for 18 h. The solution is cooled of the raw product and is divided between water and EtOAc. Wash the organic phase separated with brine, dried (Na2SO4) and It leaks. The product is purified by column chromatography a through silica gel using eluent MeOH as a mixture in methylene chloride, in this way the compound is obtained desired intermediate tetrahydrofuranylmethylaminopyrimidine ether in pink foam form (278 mg, 66%).

Similarly, the (R) enantiomer of the tetrahydrofurfurylamine (0.13 ml) allows obtaining the enantiomer opposite in a yield of 76%.

The hydrochloride of the 3-amino-5-tert-butyl-2- (p-tolyl) -2H-pyrazole (59 mg, 0.22 mmol, 1 equiv.) In 12 ml methylene chloride and you will be add 12 ml of a saturated aqueous solution of NaHCO3. Be Stir the biphasic mixture until the solids have dissolved completely and cooled to 0 ° C. The organic phase is treated with phosgene in one serving with an un shaken syringe (0.40 ml of a 20% solution in toluene, 0.78 mmol, 3.5 equiv.). It shakes vigorously the resulting mixture at 0 ° C for 0.5 h. The organic phase, dried (Na2SO4) and filtered. It is eliminated the methylene chloride under vacuum and the isocyanate is treated resulting in toluene with a solution of the previous compound intermediate tetrahydrofuranylmethylaminopyrimidine ether (75 mg, 0.22 mmol, 1.0 equiv.) In 4 ml of anhydrous THF. The mixture is stirred at room temperature for 36 h, then the solvent with vacuum. The product is purified by chromatography of column through silica gel using as eluent mixture the MeOH from 0 to 10% in methylene chloride, obtaining 112 mg of epigraphy compound [enantiomer (S)] in foam form slightly pink Subsequent purification by preparatory HPLC in reverse phase it allows to obtain 44 mg of the epigraph compound in pure yellow foam shape.

The synthesis of the enantiomer (R) is carried out applying exactly the same procedure as just describe, but using the opposite enantiomer of the compound intermediate tetrahydrofuranylmethylaminopyrimidine ether.

Evaluation of biological properties Inhibition of TNF production in THP cells

Inhibition of cytokine production is observed by measuring TNFα inhibition in THP cells stimulated with lipopolysaccharides (see for example W. Prichett et al., J. Inflammation 45 , 97, 1995). All cells and reagents are diluted in RPMI 1640 with phenol red and L-glutamine, supplemented with additional L-glutamine (total: 4 mM), penicillin and streptomycin (50 units / ml each) and fetal bovine serum (FBS, 3%) (GIBCO, all indicated as final conc.). The test is performed under sterile conditions; only the compound is obtained under non-sterile conditions. The initial standard solutions are prepared in DMSO and then diluted in RPMI 1640 2 times greater than the final concentration desired for the assay. Confluent THP.1 cells (2x10 6 cells / ml, final conc; American Type Culture Company, Rockville, MD) are added to 96-hole round bottom polypropylene culture plates (Costar 3790; sterile) containing 125 µl of the compound to be tested (2 times higher concentration) or DMSO vehicle (controls, blank samples). The concentration of DMSO should not exceed the final 0.2%. The cell mixture is pre-incubated at 37 ° C for 30 min, with 5% CO 2 before stimulation with lipopolysaccharides (LPS; 1 µg / ml final; Follow L-2630, serotype 0111.B4 of E. coli stored in the form of 1 mg / ml standard in distilled H2O analyzed in its endotoxin content at -80 ° C). Blank samples (not stimulated) receive H2O as a vehicle; The final incubation volume is 250 µl. Incubation is performed overnight (18-24 h) in the manner described above. The test is terminated by centrifuging the plates at room temperature for 5 min, at 1600 rpm (400 xg); Supernatants are transferred to clean 96-hole plates and stored at -80 ° C until they are analyzed for human TNFα content with a commercial ELISA kit (Biosource, No. KHC3015, Camarillo, CA). The data is analyzed with a non-linear regression (Hill equation) to generate a dose response curve using a SAS Software System (SAS Institute, Inc., Cary, NC) software. The calculated value of the IC50 is the concentration of test compound that causes a 50% decrease in the maximum production of TNFα.

Preferred compounds have an IC50 <10 µM in this assay.

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Inhibition of other cytokines

By similar methods and using peripheral blood monocytic cells, appropriate stimuli and commercial ELISA kits (or other detection method, for example the radioimmune assay), the inhibition of IL-1 beta, GM-CSF, the inhibition of IL-1 beta, can be demonstrated for a particular cytokine. IL-y6 and IL-8 causing the preferred compounds (see for example JC Lee et al., Int. J. Immunopharmacol. 10 , 835, 1988).

Claims (5)

1. A compound chosen from: 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- (4- {2- [2- (1-phenyl-ethylamino) -pyrimidin-4-yl] - ethoxy} -naphthalen-1-yl) -urea; 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- {4- [2- (cyclopropylmethyl-amino) -pyrimidin-4-yloxy] -naphthalen-1-yl }-urea; 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- (4- {2 - [(tetrahydro-furan-2-ylmethyl) -amino] -pyrimidin-4- yloxy} -naphthalen-1-yl) -urea; 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- (4- {2 - [(thiophene-2-ylmethyl) -amino] -pyrimidin-4-yloxy} -4-naphthalen-1-yl) -
urea; 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- (4- {2- [2- (1-pyridin-2-yl-ethylamino) -pyrimidin-4 -il] -ethoxy} -naphthalen-1-yl) -urea; acid ethylamide 4- (2- {4- [3- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -pyridine-2- carboxylic; acid diethylamide 4- {4- [3- (5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -pyridine-2-carboxylic acid; 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- {4- [2- (2-piperidin-1-ylmethyl-pyridin-4-yl) -ethoxy] -naftalen-1-yl} -urea; methyl phenyl amide of the acid 4- (4- {3- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -ureido} -naphthalen-1-yloxy) -pyridine- 2-carboxylic; 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- (4- {2- [2- (1-phenyl-ethylamino) -pyrimidin-4-yloxy] - ethyl} -naphthalen-1-yl) -urea; acid ethylamide 4- (2- {4- [3- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -morpholine-2- carboxylic; 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- {4- [2- (2-diethylaminomethyl-morpholin-4-yl) -ethoxy] -naphthalen-1 -il} -urea; methyl phenyl amide of the acid 4- (2- {4- [3- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -morpholine-2- carboxylic; 1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- (4- {2- [2- (1-phenyl-ethylamino) -pyrimidin-4-yl] -ethoxy} -naftalen-1-yl) -urea; 1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3-4- [2- (cyclopropylmethyl-amino) -pyrimidin-4-yloxy] -naphthalen-1-yl} -urea ; 1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- (4- {2 - [(tetrahydro-furan-2-ylmethyl) -amino] -pyrimidin-4-yloxy} -naftalen-1-yl) -urea; 1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- (4- {2 - [(thiophen-2-ylmethyl) -amino] -pyrimidin-4-yloxy} -naphthalen -1-yl) -urea; 1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- (4- {2- [2- (1-pyridin-2-yl-ethylamino) -pyrimidin-4-yl ] -ethoxy} -naphthalen-1-yl) -urea; acid ethylamide 4- (2- {4- [3- (5-tert-Butyl-2-methyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -pyridine-2-carboxylic acid; acid diethylamide 4- {4- [3- (5-tert-Butyl-2-methyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -pyridine-2-carboxylic acid; 1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- {4- [2- (2-piperidin-1-ylmethyl-pyridin-4-yl) -ethoxy] -naphthalen -1-yl} -urea; 1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- (4- {2- [2- (1-phenyl-ethylamino) -pyrimidin-4-yloxy] -ethyl} -naftalen-1-yl) -urea; 4- (2- {4- [3- (5-tert-Butyl-2-methyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -morpholine-2 acid ethylamide -
carboxylic; 1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- {4- [2- (2- diethylaminomethyl-morpholin-4-yl) -ethoxy] -naphthalen-1-yl} -urea; methyl phenyl amide of the acid 4- (2- {4- [3- (5-tert-Butyl-2-methyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -morpholine-2-carboxylic acid; acid methylamide 4- (2- {4- [3- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -morpholine-2- carboxylic; acid dimethylamide 4- (2- {4- [3- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -morpholine-2- carboxylic; acid phenylamide 4- (2- {4- [3- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -morpholine-2- carboxylic; 2- [4- (2- {4- [3- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -morpholin -2-yl] -N, N-dimethyl-
acetamide; 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- {4- [2- (2-phenyl-morpholin-4-yl) -ethoxy] -naphthalen-1 -il} -urea; 1- {4- [2- (2-Benzyl-morpholin-4-yl) -ethoxy] -naphthalen-1-yl} -3- (5-tert-butyl-2-p-tolyl-2H-pyrazole-3 -il) -urea; 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- {4- [2- (2-phenethyl-morpholin-4-yl) -ethoxy] -naphthalen-1 -il} -urea; 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- {4- [2- (2-phenoxymethyl-morpholin-4-yl) -ethoxy] -naphthalen-1 -il} -urea; 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- (4- {2- [2- (1-phenyl-ethyl) -morpholin-4-yl] - ethoxy} -naphthalen-1-yl) -urea; 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- {4- [2- (2-oxa-5-aza-bicyclo [2.2.1] hept-5 -yl) -ethoxy] -naphthalen-1-yl} -urea; 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- {4- [2- (2-thiazol-2-yl-morpholin-4-yl) -ethoxy] -naftalen-1-yl} -urea; 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- {4- [2- (2,3-dihydro-benzo [1,4] oxazin-4-yl ) -ethoxy] -naphthalen-1-yl} -urea; acid methylamide 4- (2- {4- [3- (5-tert-Butyl-2-methyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -morpholine-2-carboxylic acid; acid methylamide 4- (2- {4- [3- (5-tert-Butyl-2-methyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -morpholine-2-carboxylic acid; acid dimethylamide 4- (2- {4- [3- (5-tert-Butyl-2-methyl-2H-pyrazol-3-yl) ureido] -naphthalen-1-yloxy} -ethyl) -morpholine-2-carboxylic acid; acid phenylamide 4- (2- {4- [3- (5-tert-Butyl-2-methyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy) -ethyl) -morpholine-2-carboxylic acid; 2- [4- (2- {4- [3- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -morpholin-2 -yl] -N, N-dimethyl-acetamide; 1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- {4- [2- (2-phenyl-morpholin-4-yl) -ethoxy] -naphthalen-1-yl }-urea; 1- {4- [2- (2-Benzyl-morpholin-4-yl) -ethoxy] -naphthalen-1-yl} -3- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl )-urea; 1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- {4- [2- (2-phenethyl-morpholin-4-yl) -ethoxy] -naphthalen-1-yl }-urea; 1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- {4- [2- (2-phenoxymethyl-morpholin-4-yl) -ethoxy] -naphthalen-1-yl )-urea; 1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- (4- {2- [2- (1-phenyl-ethyl) -morpholin-4-yl] -ethoxy} -naftalen-1-yl) -urea; 1- (5-tert-butyl-2- (6-methoxy-pyridin-3-yl) -2H-pyrazol-3-yl) -3- {4- [2- (2,3-dihydro-benzo [1 , 4] oxazin-4-yl) -ethoxy] -
naphthalen-1-yl} -urea; 1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- {4- [2- (2-thiazol-2-yl-morpholin-4-yl) -ethoxy] -naphthalen -1-yl} -urea; 1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- {4- [2- (2,3-dihydro-benzo [1,4] oxazin-4-yl) - ethoxy] -naphthalen-1-yl} -urea; 4- [2- (4- {3- [5-tert-Butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -ureido} -naphthalen-1 acid methylamide -yloxy) -
ethyl] -morpholine-2-carboxylic; methyl phenyl amide of the acid 4- [2- (4- {3- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -ureido} -naphthalen-1-yloxy) -ethyl] -morpholine-2-carboxylic; acid dimethylamide 4- [2- (4- {3- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -ureido} -naphthalen-1-yloxy) -ethyl] -morpholine-2-carboxylic;

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4- [2- (4- {3- [5-tert-Butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -ureido} -naphthalen-1 acid phenylamide -yloxy) -
ethyl] -morpholine-2-carboxylic; 2- {4- [2- (4- {3- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -ureido} -naphthalen-1 -yloxy) -ethyl] -morpholin-2-yl} -N, N-dimethyl-acetamide; 1- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- {4- [2- (2-phenyl-morpholin-4-yl ) -ethoxy] -naphthalen-1-yl} -urea; 1- {4- [2- (2-Benzyl-morpholin-4-yl) -ethoxy] -naphthalen-1-yl} -3- [5-tert-butyl-2- (6-methyl-pyridin-3- il) -2H-pyrazol-3-yl] -urea; 1- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- {4- [2- (2-phenethyl-morpholin-4-yl ) -ethoxy] -naphtalen-1-yl} -
urea; 1- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- {4- [2- (2-phenoxymethyl-morpholin-4-yl ) -ethoxy] -naphthalen-1-yl} -urea; 1- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- (4- {2- [2- (1-phenyl-ethyl) -morpholin-4-yl] -ethoxy} -naphthalen-1-
il) -urea; 1- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- {4- [2- (2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl) -ethoxy] -naphthalen-1-yl} -urea; 1- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- {4- [2- (2-thiazol-2-yl-morpholin-4-yl) -ethoxy] -naphthalen-1-yl} -urea; 1- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- {4- [2- (2,3-dihydro-benzo [1 , 4] oxazin-4-yl) -ethoxy] -naphtha-
len-1-yl} -urea; 1- [5-tert-butyl-2- (6-methoxy-pyridin-3-yl) -2H-pyrazol-3-yl] -3- {4- [2- (2-phenethyl-morpholin-4-yl ) -ethoxy] -naphtalen-1-yl} -
urea; 1- [5-tert-butyl-2- (6-methoxy-pyridin-3-yl) -2H-pyrazol-3-yl] -3- (4- [2- (2-phenoxymethyl-morpholin-4-yl ) -ethoxy] -naftalen-1-
il} -urea; 1- [5-tert-butyl-2- (6-methoxy-pyridin-3-yl) -2H-pyrazol-3-yl] -3- (4- {2- [2- (1-phenyl-ethyl) -morpholin-4-yl] -ethoxy} -naphthalen-1-yl) -urea; 1- [5-tert-butyl-2- (6-methoxy-pyridin-3-yl) -2H-pyrazol-3-yl] -3- {4- [2- (2-oxa-5-aza-bike) [2.2.1] hept-5-yl) -ethoxy] -naphthalen-1-yl} -urea; 1- [5-tert-butyl-2- (6-methoxy-pyridin-3-yl) -2H-pyrazol-3-yl] -3- {4- [2- (2-thiazol-2-yl-morpholin) -4-yl) -ethoxy] -naphthalen-1-
il} -urea; 1- [5-tert-butyl-2- (6-methoxy-pyridin-3-yl) -2H-pyrazol-3-yl] -3- {4- [2- (2,3-dihydro-benzo [1 , 4] oxazin-4-yl) -ethoxy] -naphthalen-1-yl} -urea; 1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- {4- [2- (cyclopropylmethyl-amino) -6-methyl-pyrimidin-4-yloxy] -naphthalen-1 -
il} -urea; 1- (5-tert-butyl-2- {2-methyl-pyrimidin-5-yl) -3- {4- [2- (cyclopropylmethyl-amino) -pyrimidin-4-yloxy] -ethyl} -naphthalen-1 -il) -
urea and 1- (5-tert-butyl-2- {2-methyl-pyrimidin-5-yl) -3- {4- [2- (cyclopropylmethyl-amino) -6-methyl-pyrimidin-4-yloxy] -ethyl} -naphtha-
len-1-il) -urea, or pharmaceutically acidic or salts Acceptable of them.

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2. A compound according to claim 1, chosen from: 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- (4- {2- [2- (1-phenyl-ethylamino) -pyrimidin-4-yl] - ethoxy} -naphthalen-1-yl) -urea; 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- {4- [2- (cyclopropylmethyl-amino) -pyrimidin-4-yloxy] -naphthalen-1-yl }-urea; 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- (4- {2 - [(tetrahydro-furan-2-ylmethyl) -amino] -pyrimidin-4- yloxy} -naphthalen-1-yl) -urea; 1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- (4- {2- [2- (1-pyridin-2-yl-ethylamino) -pyrimidin-4 -il] -ethoxy} -naphthalen-1-yl) -urea; acid ethylamide 4- (2- {4- [3- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -pyridine-2- carboxylic; acid diethylamide 4- {4- [3- (5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -pyridine-2-carboxylic acid; methyl phenyl amide of the acid 4- (4-3- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -ureido} -naphthalen-1-yloxy) -pyridine-2 -carboxylic; acid ethylamide 4- (2- {4- [3- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -morpholine-2- carboxylic; methyl phenyl amide of the acid 4- (2- {4- [3- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -morpholine-2- carboxylic; acid methylamide 4- (2- {4- [3- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -morpholine-2- carboxylic; acid dimethylamide 4- (2- {4- [3- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -ethyl) -morpholine-2- carboxylic; acid phenylamide 4- (2- {4- [3- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -ureido] -naphthalen-1-yloxy} -eti1) -morpholine-2- carboxylic; 4- [2- (4- {3- [5-tert-Butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -ureido} -naphthalen-1 acid methylamide -yloxy) -
ethyl] -morpholine-2-carboxylic; methyl phenyl amide of the acid 4- [2- (4- {3- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -ureido} -naphthalen-1-yloxy) -ethyl] -morpholine-2-carboxylic; acid dimethylamide 4- [2- (4- {3- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -ureido} -naphthalen-1-yloxy) -ethyl] -morpholine-2-carboxylic; 4- [2- (4- {3- [5-tert-Butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -ureido} -naphthalen-1 acid phenylamide -yloxy) -
ethyl] -morpholine-2-carboxylic; 1- {4- [2- (2-Benzyl-morpholin-4-yl) -ethoxy] -naphthalen-1-yl} -3- [5-tert-butyl-2- (6-methyl-pyridin-3- il) -2H-pyrazol-3-yl] -urea; 1- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- {4- [2- (2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl) -ethoxy] -naphthalen-1-yl} -urea; 1- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- {4- [2- (2,3-dihydro-benzo [1 , 4] oxazin-4-yl) -ethoxy} -naphtha-
len-1-yl} -urea; 1- [5-tert-butyl-2- (6-methoxy-pyridin-3-yl) -2H-pyrazol-3-yl] -3- {4- [2- (2-oxa-5-aza-bike) [2.2.1] hept-5-yl) -ethoxy] -naphthalen-1-yl} -urea; 1- [5-tert-butyl-2- (6-methoxy-pyridin-3-yl) -2H-pyrazol-3-yl] -3- {4- [2- (2,3-dihydro-benzo [1 , 4] oxazin-4-yl) -ethoxy] -naphthalen-1-yl} -urea; 1- (5-tert-butyl-2- {2-methyl-pyrimidin-5-yl) -3- {4- [2- (cyclopropylmethyl-amino) -pyrimidin-4-yloxy] -ethyl} -naphthalen-1 -il) -
urea and 1- (tert-butyl-2- {2-methyl-pyrimidin-5-yl) -3- {4- [2- (cyclopropylmethyl-amino) -6-methyl-pyrimidin-4-yloxy] -ethyl} -naphthalen -1-il) -urea, or pharmaceutically acidic or salts Acceptable of them.

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3. A pharmaceutical composition that contains a pharmaceutically effective amount of a compound according to the claim 1 and one or more vehicles and / or adjuvants pharmaceutically acceptable. 4. A compound according to claim 1, for treat a disease or disease condition chosen among arthritis rheumatoid, inflammatory bowel disease, the osteoarthritis, Crohn's disease, ulcerative colitis, Psoriasis and chronic obstructive pulmonary disease. 5. Use of a pharmaceutical composition that contains a pharmaceutically effective amount of a compound according to claim 1 for manufacturing a medicament intended to be treated a disease or pathological condition chosen from inflammatory, the osteoarthritis, Crohn's disease, ulcerative colitis, Psoriasis and chronic obstructive pulmonary disease.